rs41288981

chr6-137204389-G-Achr6-137204389-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000416.3(IFNGR1):c.489C>T(p.Pro163=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00818 in 1,613,648 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0084 (75 hom.)
• Consequence: IFNGR1 NM_000416.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.593

Genes affected

IFNGR1 (HGNC:5439): (interferon gamma receptor 1) This gene (IFNGR1) encodes the ligand-binding chain (alpha) of the gamma interferon receptor. Human interferon-gamma receptor is a heterodimer of IFNGR1 and IFNGR2. A genetic variation in IFNGR1 is associated with susceptibility to Helicobacter pylori infection. In addition, defects in IFNGR1 are a cause of mendelian susceptibility to mycobacterial disease, also known as familial disseminated atypical mycobacterial infection. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-137204389-G-A is Benign according to our data. Variant chr6-137204389-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 36375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-137204389-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.593 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00639 (973/152202) while in subpopulation NFE AF= 0.00975 (663/68010). AF 95% confidence interval is 0.00913. There are 3 homozygotes in gnomad4. There are 482 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFNGR1	NM_000416.3	c.489C>T	p.Pro163=	synonymous_variant	4/7	ENST00000367739.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFNGR1	ENST00000367739.9	c.489C>T	p.Pro163=	synonymous_variant	4/7	1	NM_000416.3	P2

Frequencies

GnomAD3 genomes AF: 0.00641 AC: 975 AN: 152084 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0204

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00975

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00631 AC: 1587 AN: 251366 Hom.: 16 AF XY: 0.00645 AC XY: 876 AN XY: 135852

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.0193

Gnomad NFE exome AF: 0.00933

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00837 AC: 12229 AN: 1461446 Hom.: 75 Cov.: 31 AF XY: 0.00813 AC XY: 5914 AN XY: 727044

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000487

Gnomad4 FIN exome AF: 0.0203

Gnomad4 NFE exome AF: 0.00950

Gnomad4 OTH exome AF: 0.00729

GnomAD4 genome AF: 0.00639 AC: 973 AN: 152202 Hom.: 3 Cov.: 32 AF XY: 0.00648 AC XY: 482 AN XY: 74424

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0204

Gnomad4 NFE AF: 0.00975

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00887 Hom.: 0

Bravo AF: 0.00482

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00785

EpiControl AF: 0.00871

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Disseminated atypical mycobacterial infection Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Interferon gamma receptor deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing;curation

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

IFNGR1: BP4, BP7, BS2 -

Immunodeficiency 27A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.56
Dann	Benign	0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs41288981; hg19: chr6-137525526;